The aim of this study is to investigate selected areas of the neurobiology of depression. Depressed patients free of psychotropic medications for at least two weeks are evaluated, diagnosed and symptoms rated on the 4-East Clinical Research Unit of the NIH Clinical Center. During the past year we have attempted to assess neurotransmitter function in depression by measuring levels of amine and amine metabolites in plasma and cerebrospinal fluid (CSF) in depressed patients and normal controls. We have observed higher levels of circulating plasma norepinephrine in unipolar patients with DSM-III diagnosed melancholia in comparison to controls. We have also found that melancholic patients have lower levels of CSF homovanillic acid (HVA) and 3,4-dihyddroxyphenylacetic acid (DOPAC) then nonmelancholic depressed patients although we also observed that depressed patients who have experienced life events prior to the onset of depression tended not to have low levels of these CSF metabolites. These data suggest activation of the sympathetic nervous system and diminished CNS dopaminergic system function, respectively, in patients with melancholia. We have also studied underlying mechanisms involved in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, a disturbance found in many depressed patients. We have observed that nonsuppression to the dexamethasone suppression test (DST) is associated with higher levels of plasma norepinephrine and with higher levels of CSF 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). We have also found that low levels of the brain peptide, somatostatin, are associated with DST nonsuppression. An experimental paradigm in humans intended to invoke a transitory experience of learned helplessness as a model for depression has also been initiated.